Dystrophin Deficiency Causes Hyper-Secretion and Atrophy in Myotubes

Stephanie Duguez, Helen Johnston, Douglas Johnson, Kristy Brown, Yetrib Hathout, Terence Partridge

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

The generally accepted view of the pathology of Duchenne muscular dystrophy is that absence of dystrophin renders myofibres abnormally susceptible to work-induced trauma, precipitating recurrent bouts of segmental myofibre necrosis. Necrosis stimulates inflammation and a regenerative response by myoblasts; the latter gradually becoming ineffective due to exhaustion of cells and accumulation of connective tissue driven by chronic inflammation. However, while searching for biomarkers in tissue cultures of dystrophic mouse muscle, we found phenomena that cause us to revise this picture. Using stable isotope labeled amino acids (SILAC) combined with liquid chromatography tandem mass spectrometry, we found that undamaged dystrophic myotubes are hypersecretive, excessively effluxing 57 intracellular proteins by mechanisms that cannot be identified as cell death, or generalized increase in passive leakiness. In addition dystrophic myotubes were smaller than wild-type and contain less protein and RNA per nucleus. We hypothesize that lack of dystrophin, as well as predisposing the myofibre to necrosis during physiological stress, has more profound general effects on its metabolic balance and its relationship with the extracellular environment, these potentially contributing to progressive muscle pathology. We identify myosin light chain 1 as a biomarker for in vitro drug screening.
LanguageEnglish
Title of host publicationUnknown Host Publication
Pages1051-27
Number of pages2000
Volume25
Publication statusAccepted/In press - 9 Feb 2011
EventExperimental Biology 2011 -
Duration: 9 Feb 2011 → …

Conference

ConferenceExperimental Biology 2011
Period9/02/11 → …

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Dystrophin
Skeletal Muscle Fibers
Atrophy
Necrosis
Biomarkers
Pathology
Inflammation
Connective Tissue Cells
Muscles
Myosin Light Chains
Preclinical Drug Evaluations
Physiological Stress
Duchenne Muscular Dystrophy
Myoblasts
Tandem Mass Spectrometry
Liquid Chromatography
Isotopes
Proteins
Cell Death
RNA

Keywords

  • Muscle secretome
  • SILAC
  • DMD

Cite this

Duguez, S., Johnston, H., Johnson, D., Brown, K., Hathout, Y., & Partridge, T. (Accepted/In press). Dystrophin Deficiency Causes Hyper-Secretion and Atrophy in Myotubes. In Unknown Host Publication (Vol. 25, pp. 1051-27)
Duguez, Stephanie ; Johnston, Helen ; Johnson, Douglas ; Brown, Kristy ; Hathout, Yetrib ; Partridge, Terence. / Dystrophin Deficiency Causes Hyper-Secretion and Atrophy in Myotubes. Unknown Host Publication. Vol. 25 2011. pp. 1051-27
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Duguez, S, Johnston, H, Johnson, D, Brown, K, Hathout, Y & Partridge, T 2011, Dystrophin Deficiency Causes Hyper-Secretion and Atrophy in Myotubes. in Unknown Host Publication. vol. 25, pp. 1051-27, Experimental Biology 2011, 9/02/11.

Dystrophin Deficiency Causes Hyper-Secretion and Atrophy in Myotubes. / Duguez, Stephanie; Johnston, Helen; Johnson, Douglas; Brown, Kristy; Hathout, Yetrib; Partridge, Terence.

Unknown Host Publication. Vol. 25 2011. p. 1051-27.

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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AU - Brown, Kristy

AU - Hathout, Yetrib

AU - Partridge, Terence

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AB - The generally accepted view of the pathology of Duchenne muscular dystrophy is that absence of dystrophin renders myofibres abnormally susceptible to work-induced trauma, precipitating recurrent bouts of segmental myofibre necrosis. Necrosis stimulates inflammation and a regenerative response by myoblasts; the latter gradually becoming ineffective due to exhaustion of cells and accumulation of connective tissue driven by chronic inflammation. However, while searching for biomarkers in tissue cultures of dystrophic mouse muscle, we found phenomena that cause us to revise this picture. Using stable isotope labeled amino acids (SILAC) combined with liquid chromatography tandem mass spectrometry, we found that undamaged dystrophic myotubes are hypersecretive, excessively effluxing 57 intracellular proteins by mechanisms that cannot be identified as cell death, or generalized increase in passive leakiness. In addition dystrophic myotubes were smaller than wild-type and contain less protein and RNA per nucleus. We hypothesize that lack of dystrophin, as well as predisposing the myofibre to necrosis during physiological stress, has more profound general effects on its metabolic balance and its relationship with the extracellular environment, these potentially contributing to progressive muscle pathology. We identify myosin light chain 1 as a biomarker for in vitro drug screening.

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Duguez S, Johnston H, Johnson D, Brown K, Hathout Y, Partridge T. Dystrophin Deficiency Causes Hyper-Secretion and Atrophy in Myotubes. In Unknown Host Publication. Vol. 25. 2011. p. 1051-27